This competitive renewal application for a K24 will enable Dr. Kranzler to continue his career development, mentorship of beginning clinical investigators, and research in the pharmacotherapy and pharmacogenetics of alcohol dependence. The research plan includes three projects, two of which are currently funded by NIAAA and one of which is under scientific review at NIAAA. The ultimate research goal of the proposal is to synthesize psychopharmacologic and genetic methods and findings to yield a coherent pharmacogenetic approach to the etiology and treatment of alcoholism. The specific research aims of the proposal are to 1) complete data collection, analysis, and report preparation for a placebo-controlled study of targeted naltrexone for problem drinkers, 2) complete data collection, analysis, and report preparation for a placebo-controlled study of sertraline for alcoholism subtypes, and 3) conduct a placebo-controlled trial of topiramate for problem drinkers. The mentoring plan will focus on the training of graduate and medical students, psychiatric residents, postdoctoral, and junior faculty to conduct patient-oriented alcohol research. The training will focus on clinical research methods, data interpretation, manuscript and grant preparation, research ethics, and human subjects protections. Mentoring will occur through trainees' participation in Dr. Kranzler's and their own research projects and through lectures and seminars offered through the Alcohol Research Center, Department of Psychiatry, and the General Clinical Research Center at the University of Connecticut School of Medicine. This range of research and educational activities offers a rich matrix of opportunities for trainees and junior investigators in patient-oriented research. The training plan identifies coursework and training experiences for Dr. Kranzler in areas that are important to Dr. Kranzler's continued development as an investigator and mentor. Over the next five years, the candidate seeks to: 1) maintain full-time effort in research and research mentoring, 2) increase the depth and breadth of his own skills through specific training in genetics, biostatistics, and bioinformatics and through continued collaboration with established experts in these areas, 3) continue the widespread dissemination of research findings through presentation at scientific meetings and publication in the scientific literature and 4) help to train the next generation of investigators who will advance the field of patient-oriented alcohol research. Relevance to public health: The proposal focuses on novel treatments for problem drinking and alcohol dependence. New findings in these areas will improve outcomes for people with these conditions. The proposal will also contribute insights into the genetic risk for alcohol dependence and moderators of treatment response, which have implications both for prevention and treatment of the disorder.